1. Medical Research Council Laboratory of Molecular Biology, Hills Road, Cambridge CB2 2QH, UK

Correspondence to: Michael S. Neuberger Correspondence and requests for materials should be addressed to M.S.N. (e-mail: Email: msn@mrc-lmb.cam.ac.uk).

Abstract

A functional immune system depends on the production of a wide range of immunoglobulin molecules. Immunoglobulin variable region (IgV) genes are diversified after gene rearrangement by hypermutation. In the DNA deamination model, we have proposed that deamination of dC residues to dU by activation-induced deaminase (AID) triggers this diversification. In hypermutating chicken DT40 B cells, most IgV mutations are dC dG/dA or dG dC/dT transversions, which are proposed to result from replication over sites of base loss produced by the excision activity of uracil-DNA glycosylase. Blocking the activity of uracil-DNA glycosylase should instead lead to replication over the dU lesion, resulting in dC dT (and dG dA) transitions. Here we show that expression in DT40 cells of a bacteriophage-encoded protein that inhibits uracil-DNA glycosylase shifts the pattern of IgV gene mutations from transversion dominance to transition dominance. This is good evidence that antibody diversification involves dC dU deamination within the immunoglobulin locus itself.

1. Medical Research Council Laboratory of Molecular Biology, Hills Road, Cambridge CB2 2QH, UK

Correspondence to: Michael S. Neuberger Correspondence and requests for materials should be addressed to M.S.N. (e-mail: Email: msn@mrc-lmb.cam.ac.uk).